AdvancedMensNaturalHormoneBalancing JM …...Testosterone Declines at 1.6% Per Year Starting at Age 30! So at an age when many men are just figuring out what they want to be when they

Men’s Health:In Addition to TestosteroneAdvanced Solutions for Insulin Resistance, Metabolic Syndrome and Andropause

Jay H. Mead, MDMedical DirectorLabrix Clinical Services, Inc.

Learning objectives

• Review the role of testosterone in men’s health• Examine the process and consequences of andropauseincluding metabolic syndrome

• Review the roles of estrogen and progesterone in male physiology

• Explore natural therapies to treat hormonal changes in men• Discuss risks and benefits of testosterone replacement• Evaluate the role of DHT with prostate health

Testosterone Declines at 1.6% Per Year Starting at Age 30!

So at an age when many men are just figuring out what they want to be when they “grow up” or are starting a family, their testosterone levels are already declining.

Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle‐aged men: longitudinal results from the Massachusetts male aging study. J Clin EndocrinolMetab. 2002 Feb; 87(2): 589‐598.

TESTOSTERONE is the key to life for men…PERIOD

Testosterone has been studied and used since 1939; before there was an F.D.A.

Staying Healthyis

Staying Anabolic!

Laughlin GA, et al. Low serum testosterone and mortality in older men. J Clin EndocrinolMetab. 2008; 93: 68‐75.

Symptoms and Signs

• Apathy/ lack of motivation• Night sweats• Hot flashes • Decreased flexibility• Loss of muscle mass• Weight gain – waist • Reduced libido• Burned out feeling• Erectile dysfunction• Fatigue

Grave consequences

• Low testosterone leads to:• Insulin resistance• Hypertension• Diabetes• High cholesterol• Elevated triglycerides• Heart disease• Depression

Pines A. Male menopause: is it a real clinical syndrome? Climacteric. 2011; 14: 15‐17.

ED patients are the lucky ones!2008 epidemiologic study looked at the relationship between erectile dysfunction, metabolic syndrome and cardiovascular disease. ED is the symptom that prompts many men to seek treatment; and that treatment could save their lives.

Corona G, et al. Why can patients with erectile dysfunction be considered lucky? The association with testosterone deficiency and metabolic syndrome. Aging Male. 2008; 11: 193‐9.

Insulin Resistance• Low testosterone increases adiposity.•Abdominal adipose tissue is more insulin resistant.

• Leptin produced by adipose may reduce testoserone production.

•Obesity causes reduction in LH.

Kapoor D, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006; 154: 899‐06.

Insulin Resistance, Estrogen and Testosterone

↑Estrogen

↑SHBG↓Test

↑ Adipose↑Insulin Resistance

↓LH

Insulin Resistance•One of greatest risks of low testosterone

•Pre‐diabetic condition•Occurs when cell membrane/ receptors become resistant to insulin and no longer let glucose into the cell

Kapoor D, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006; 154: 899‐06.

“… data from intervention studies suggest that the low secretion of testosterone might be a primary event in the pathogenesis of insulin resistance, because the replacement of testosterone to normal values reverts insulin resistance”

Tibblin G, et al. The pituitary‐gonadal axis and health in elderly men: a study of men born in 1913. Diabetes. 1996; 45: 1605‐9.

Low Testosterone Leads to Insulin Resistance

• Diabetes• Inflammation• Stroke• CAD• Hypertension• Urinary tract infections

• BPH• Malignancies• ED• Infertility

Insulin Resistance Leads To:

Insulin Resistant (Metabolic) Syndrome• Metabolic syndrome is a name for a group of risk factors that occur together and increase the risk for coronary artery disease, stroke and type 2 diabetes.

• According to International Diabetes Federation (IDF) a definition of metabolic syndrome must include central obesity plus any two of the following four factors:

• Fasting glucose: >100 or Rx for type II diabetes• Triglyceride: >150 • HDL: <40 male; <50 female• Hypertension: >130 systolic, >85 diastolic

• Low Testosterone?International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. Available at: http://www.idf.org/webdata/docs/IDF_Meta_def_final.pdf. Accessibility verified December 23, 2014.

Epidemiology Of Metabolic Syndrome (MetS)

•35% to 39% of US adult population: males and females essentially equal

•32% of adult population obese•Past 30 years obesity doubled in children

• T2DM accounts 20% to 25% childhood DM

Gorbachinsky I, et al. Metabolic syndrome and urologic diseases. Rev Urol. 2010; 12: e157‐e180.

Pre US visit Post 2 year US visit

Metabolic syndrome and hypogonadism

• Diminished testosterone associated with HTN, obesity, hyperinsulinemia, T2DM, hyperglycemia, HbA1c, triglyceridemia, elevated CRP and low HDL

• All parameters improve with weight loss• All parameters improve with testosterone supplementation

• Leptin resistance may be a key playerGorbachinsky I, et al. Metabolic syndrome and urologic diseases. Rev Urol. 2010; 12: e157‐e180.

Metabolic syndrome and hypogonadism

• Leptin secreted by adipocytes and regulates energy utilization and intake via the hypothalamus

• Directly associated with BMI• Inversely associated with testosterone levels by reducing LH

• Testosterone injections lower leptin levels


Metabolic Syndrome

The ‘tip of the iceberg’ to the commonality of most disease states

• Measure Cholesterol• Take weight• Take blood pressure• Measure glucose• Measure INSULIN

• >10miu/L!!

Alberti KGMM, et al. Harmonizing the metabolic syndrome. Circulation. 2009; 120: 1640‐45.

Metabolic Syndrome can lead to . . . Diabetes

Adult Onset Diabetes Mellitus

• Hyperglycemia and Hyperinsulinemia precedes• Diabetes:

• Obesity• Heart Disease• Retinopathy• Renal failure• Gangrene

• Shortened life expectancyby up to 10 years!

MetS and cardiovascular disease

•3.7 fold increase CHD•24.5 fold increase in T2DM

Gorbachinsky I, et al. Metabolic syndrome and urologic diseases. Rev Urol. 2010; 12(4): e157‐e180.

ONE DISEASEMetabolic Syndrome

•Diabetes

•Obesity

•Angina: Heart Disease• High cholesterol• High blood pressure• HIGH FASTING INSULIN• HIGH INSULIN RESISTANCE

Alberti KGMM, et al. Harmonizing the metabolic syndrome. Circulation. 2009; 120: 1640‐45.

“Waist Circumference And Mortality”

• 154,776 men, 90,757 woman prospectively studied for 9 years (1996‐2005)

• “The finding that persons with a normal BMI but a large waist circumference had a higher mortality risk in this study suggests that increased waist circumference should be considered a risk factor for mortality, in addition to BMI.”

Koster A, et al. Waist circumference and mortality. Am J Epidemiol. 2008; 167: 1465‐75.

MetS And Inflammation

• Increases in CRP and proflammatory cytokines: IL‐1,IL‐6 and TNf‐

• Fat cells release chemokines leading to macrophage infiltration and release of CRP, IL‐1, IL‐6, IL‐8 and TNf‐ contributing to IR

• Conclusion: MetS is a pro‐inflammatory state


Inflammation Affects Testosterone

• TNF‐ inhibits Leydig cell steroidogenesis• IL‐1 inhibits side chain cleavage by P450 reducing testosterone synthesis


In elderly men, low plasma testosterone is associated with elevated carotid intima‐media thickness only in those with low‐grade inflammation. Traditional risk factors have no mediator role.

Soisson V, Brailly‐Tabard S, Empana JP, et al. Low plasma testosterone and elevated carotid intima‐media thickness: importance of low‐grade inflammation in elderly men. Atherosclerosis. 2012 Jul; 223(1): 244‐9.

Benign Prostatic Hyperplasia (BPH)

• HTN, T2DM, hyperinsulinemia, abdominal obesity and dyslipidemia associated with BPH risk

• Significantly higher PSA levels are an index for prostate gland volume


Lower Urinary Tract Symptoms (LUTS)

• Elevated E2 levels significantly associated with BPH

• Increase ER in stromal cells and causes proliferation

• Increases IL‐1 and IL‐6 inducing inflammation and free radical production

• Testosterone replacement reduces LUTS

Gorbachinsky I, et al. Metabolic syndrome and urologic diseases. Rev Urol. 2010; 12: e157‐e180.Williams G. Aromatase up‐regulation, insulin and raised intracellular oestrogens in men, induce adiposity, metabolic syndrome and prostate disease, via aberrant ER‐α and GPER signaling. Mol Cell Endocrinol. 2012 Apr 4; 351(2): 269‐78. Epub 2012 Jan 5.

Erectile Dysfunction (ED)

• 3 times more prevalent in men with MetS• Increases by the number of components

• Increased waist circumference (WC): 1.94• WC, low HDL or elevated trigs: 2.97• WC, low HDL and high trigs: 3.28• Some researchers believe ED is predictive of MetS


Erectile Dysfunction (ED)

• Low testosterone is clearly associated with ED, reduced libido and reduced intercourse frequency

• Reduced nitric oxide (NO) production in penile arterial beds

• Cytokine, CRP and increased sympathetic tone also reduce NO levels

• Reduced blood flow due to CAD is also an association

• ED has 2x risk of MIGorbachinsky I, et al. Metabolic syndrome and urologic diseases. Rev Urol. 2010; 12: e157‐e180.

Infertility• BMI >25 linked increase risk; >30 3x risk

• Low sperm mobility and reduce ejaculate volume• DNA damage• Increase scrotal temperatures (scrotal lipomatosis)

• Low testosterone • LH initiates and qualitatively maintains spermatogenesis

• MetS: pro‐inflammatory states leads to increased ROS

• Membrane and DNA damage


Prostate Cancer (PCa)• Prospective Finland study of 1880 males with MetS had 2x risk of PCa

• Add BMI >27, 3x risk• Hyperglycemia 7.31• Low HDL 9.93

• Laukkanen JA etal, Cancer Epidemiol Biomarkers Prev, 2004;13:1646‐1650

• BMI>35• 2 to 3 times worse pathology findings at time of surgery• Recurrences also more likely

• Higher insulin levels: shortened survival• Membrane and DNA damage


Prostate Cancer (PCa)

• Low testosterone• More severe PCa

• Inflammatory Markers• 2 to 3 times worse pathology findings at time of surgery• Recurrences also more likely

• Higher insulin levels: shortened survival• Membrane and DNA damage

• End stage reduction of insulin production seems to reduce risk


“Metabolic Syndrome and Urologic Diseases” Gorbachinsky L, et al.

Conclusion: “Therefore, it is important for urologists to be cognizant of this disorder and the aforementioned relationships with urologic diseases.”


Testosterone and Prostate Cancer

• In 1941 Dr. Charles Huggins demonstrated that castration slowed the progression of prostate cancer.

• He assumed this was due to reduction in testosterone production.

• Reducing testosterone therefore became standard of care for prevention and treatment of prostate cancer.

Huggins C, et al. Serum phosphatase and prostatic cancer. Cancer Res. 1941; 1: 293‐297.

Testosterone Does NOT Cause Prostate Cancer

“Does Testosterone Therapy Increase the Risk of Prostate Cancer?”

Excellent Review of 27 articles• “Despite elevations in serum total and free testosterone, healthy young men do not demonstrate increased serum or semen PSA levels, or increased prostate volume in response to exogenous testosterone injections.”

Dobs AS, Morgentaler A. Does testosterone therapy increase the risk of prostate cancer? Endocr Pract. 2008; 14: 904‐11.

Testosterone Does NOT Cause Prostate Cancer

“A high prevalence of biopsy‐detectable prostate cancer was identified in men with low total or free testosterone levels despite normal PSA levels and results of digital rectal examination... (2) PSA levels may be altered by naturally occurring reductions in serum androgen levels.”Morgentaler A, et al. Occult prostate cancer in men with low serum testosterone levels. JAMA. 1996; 276: 1904‐6.

Testosterone Does Not Cause Prostate Cancer –What Does?

• Higher fasting insulin (p=0.010), HTN and prevalence of type II diabetes associated with more lethal prostate cancers. N=320 patients; 54 deaths 1995‐2003

• Hammarsten J, Hogstedt B. Eur J Cancer 2005 Dec:41(18):2887‐95

• Metabolic syndrome predicts prostate cancer in a cohort of middle‐aged Norwegian men followed for 27 years.

• Lund Haheim L. et al. Am J Epidemiol 2006 Oct 15;164(8):769‐74.

Hammarsten J, Hogstedt B. Hyperinsulinaemia: a prospective risk factor for lethal clinical prostate cancer. Eur J Cancer. 2005; 41: 2887‐95.Lund Haheim L, et al. Metabolic syndrome predicts prostate cancer in a cohort of middle‐aged Norwegian men followed for 27 years. Am J Epidemiol. 2006; 164: 769‐74.

Testosterone Does Not Cause Prostate Cancer –What Does?

• Estrogen dominance causes prostate cancer. • “Hormone Balance for Men: What Your Doctor May Not Tell You About Prostate Health and Natural Hormone Supplementation” by John Lee MD

• Recall the prostate gland has the same embryologic origin as the uterus/endometrium in the female fetus; therefore excess estradiol relative to progesterone will have same effect on the prostate mucosa, i.e., cellular proliferation

• Treatment: topical progesterone to correct a low Pg/E2 ratio

Lee JR. Hormone Balance for Men: What your Doctor May Not Tell You About Prostate Health and Natural Hormone Supplementation. Temecula, CA: One to One Inc.; 2007.

The relationship between total testosterone levels and prostate cancer: A review of the continuing controversy• Forty‐five articles studying the relationship between TT and PCa were selected.

• The preponderance of studies examining the safety of exogenous testosterone administration in men with a history of PCa would suggest that there is little, if any risk, in such a circumstance. However, the risk has not been proven to be zero, so the most prudent course is to follow such men with regular PSAs and digital rectal exams.

Klap J, et al. The relationship between total testosterone levels and prostate cancer: a review of the continuing controversy. J Urol. 2014 Sep 28. pii: S0022‐5347(14)04490‐5. doi: 10.1016/j.juro.2014.07.123. [Epub ahead of print].

Consequences of Androgen Deprivation

• Testosterone is not causing prostate cancer, however androgen deprivation therapy can lead to:

• Osteoporosis• Metabolic acidosis• Acute kidney injury• Obesity• Insulin resistance• Diabetes• Cardiovascular disease

Castration led to a reduced increase in body mass, considerable standard deviation from biochemical and histological criteria for tubular bone and, thus, an increased fracture risk. A possible cause may be reduced formation and unchanged bone loss combined with mild metabolic acidosis. Calcium and alkalization seem to be effective prophylaxis for androgen deprivation.

In a cohort of patients with newly diagnosed nonmetastatic prostate cancer, the use of ADT was significantly associated with an increased risk of AKI.

Androgen deprivation therapy increases obesity, decreases insulin sensitivity and adversely alters lipid profiles. It may be associated with a greater incidence of diabetes and cardiovascular disease.

Not Just Testosterone

• Falling testosterone levels are only part of the problem.

• Concomitant changes in other hormones also have a dramatic effect on overall health:

• Rising estrogen levels • Climbing insulin levels • Increase in SHBG • Imbalances in adrenal hormones

Aromatase• Aromatase is an adipose tissue enzyme

• Irreversibly converts testosterone to estradiol; therefore, low T and increased E2

• Increase estradiol further contributes to visceral adiposity (hypogonadal‐obesity cycle)

• E2 suppresses GnRH and reduces pituitary secretion of LH (hypogonadotropic hypogonadism—HHG)

Gorbachinsky I, et al. Metabolic syndrome and urologic diseases. Rev Urol. 2010; 12: e157‐e180.Williams G. Aromatase up‐regulation, insulin and raised intracellular oestrogens in men, induce adiposity, metabolic syndrome and prostate disease, via aberrant ER‐α and GPER signaling. Mol Cell Endocrinol. 2012 Apr 4; 351(2): 269‐78. Epub 2012 Jan 5.

SHBG is an estrogen amplifier

• SHBG increases as men age, effectively “trapping” circulating testosterone.

• SHBG preferentially binds androgens (98%), more than estrogens (90%)

• High levels of SHBG leave relatively more estradiol free.• Therefore, SHBG is an estrogen amplifier.

Burke CW, Anderson DC. Sex‐hormone‐binding globulin is an oestrogen amplifier. Nature. 1972; 240: 38‐40.

GanongWF. Review of Medical Physiology. 22nd ed. New York: McGraw‐Hill; 2005: 419‐429.HalmenschlagerG. Rhoden EL. Riedner CE. The influence of age on bioavailable and free testosterone is independent of body mass index and glucose levels. World J Urol. 2011 Aug; 29(4): 541‐6.Salonia A, et al. Circulating sex steroids and prostate cancer: introducing the time‐dependency theory. World J Urol. 2013 Apr; 31(2): 267‐73. Epub 2013 Jan 3.

Prevalence of Low Total Testosterone

• 12% for men in 50s

• 19% for men in their 60s

• 28% for men in their 70s

• 49% for men >80

Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin EndocrinolMetab. 2001; 86(2): 724‐31.

FAI=(tot T/SHBG)X0.0347=0.7‐1.0=OPTIMAL

Estrogen Dominance

• Prostate Gland Enlargement• Reduced urine flow• Urgency• Frequency

• Prostate Gland Cancer

Williams G. Aromatase up-regulation, insulin and raised intracellular oestrogens in men, induce adiposity, metabolic syndrome and prostate disease, via aberrant ER-α and GPER signaling. Mol Cell Endocrinol. 2012 Apr 4; 351(2): 269-78. Epub 2012 Jan 5.

Saliva testing

• Measure free (unbound) steroid hormone• Stress free (no needles)• Cost effective

Matsui F, et al. Liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) assay for simultaneous measurement of salivary testosterone and cortisol in healthy men for utilization in the diagnosis of late‐onset hypogonadism in males. Endocr J. 2009; 56: 1083‐93. Arregger AL, et al. Salivary testosterone: a reliable approach to the diagnosis of male hypogonadism. Clin Endocrinol(Oxf). 2007; 67: 656‐62.

Validation of Salivary Testosterone as a Screening Test for Male Hypogonadism

• Salivary collection is an easy, non‐invasive method to measure hormones.

• 1464 males aged 20 to 89: testosterone declines 47% over a lifetime

• 127 males intensely studied for sxs, total test, free test and bioavailable testosterone in relationship to salivary levels

• Results: salivary testosterone strongly correlated with bioavailability test (p<0.00001), calculated free test (p<0.0001) and total test (p<0.002)

• Conclusion: “These studies support the use of salivary testosterone as an acceptable assay for the screening for hypogonadism. Salivary testosterone is not a better assay than other measures to diagnose hypogonadism.”

Morley JE, et al. Validation of salivary testosterone as a screening test for male hypogonadism. Aging Male. 2006; 9: 165‐69.

What to test?

• Saliva• Estradiol• Progesterone• Testosterone• Cortisol

• Serum• SHBG• PSA• Lipids (triglycerides)• Fasting glucose• Fasting insulin

Treatment Approach

•Good nutrition•Regular exercise•Hormone balancing with herbs and/or hormones

Stress Relief• A recent study showed that minimal hormone concentrations of testosterone in mice corresponded to high levels of anxiety.

• Another study found that stressful conditions reduced testosterone levels in normal subjects.

• It is important to identify and relieve daily sources of stress in order to maximize the body’s ability to produce testosterone and retard the process of andropause.

Khonicheva NM, et al. Blood testosterone in rats: correlation of the level of individual anxiety and its impairment after "death threat". Neurosci Behav Physiol. 2008; 38: 985‐9.Spivak B, et al. Plasma testosterone levels in patients with combat‐related posttraumatic stress disorder. Neuropsychobiology. 2003; 47: 57‐60.

Herbs and Nutrient support

Zinc

• Required by the pituitary to release luteinizing hormone which stimulates the testes to produce testosterone

• A low‐zinc diet appears to reduce the body growth and organ weights including prostate, causing low plasma levels of luteinizing hormone and testosterone and reduction in prostate DNA replication in growing‐rats

• Zinc deficiency up regulates the aromatase enzyme

Om A, Chung K. Dietary zinc deficiency alters 5 alpha‐reduction and aromatization of testosterone and androgen and estrogen in rat liver. J Nutrition. 1996; 126: 842‐48.

Zinc

• Zinc helps to suppress aromatase and prevent conversion of testosterone to estradiol

• Research shows that zinc supplementation improves the qualitative and quantitative attributes of semen, the number of sperm per ejaculate, mass motility and semen fertility test

Kumar N, et al. Effect of different levels and sources of zinc supplementation on quantitative and qualitative semen attributes and serum testosterone level in crossbred cattle (Bosindicus x Bos taurus) bulls. Reprod Nutr Dev. 2006; 46: 663‐75.

PuncturevineTribulus terrestris

• Steroid saponins extracted from tribulus terrestris were shown to stimulate sperm production and improved sperm viability in rats

• A tribulus‐containing supplement resulted in significantly increased serum levels of androstenedione, free testosterone, estradiol and DHT

Zarkova S. [Steroid saponins of Tribulus terrestris L. have a stimulant effect on the sexual function]. Rev Port Ciencias Vet. 1984; 79: 117‐126.

Horny Goat Weed Epimedium grandiflorum

Wu H, et al. Chemical and pharmacological investigations of Epimedium species: a survey. Prog Drug Res. 2003; 60: 1‐57.Kuang AK, et al. Effects of yang‐restoring herb medicines on the levels of plasma corticosterone, testosterone and triiodothyronine. Zhong Xi Yi Jie He Za Zhi. 1989; 9: 737‐8, 710.

• Horny goat weed includes several flavonoids that act as aromatase inhibitors as well as glycosides that stimulate testosterone production.

• Epimediummay also block calcium channels causing vasodilation which can enhance erections as well as increase testosterone production.

Saw Palmetto BerrySerenoa repens

• Saw palmetto has been shown to inhibit 5‐α‐reductase activity on testosterone in vitro, thereby preventing the conversion of testosterone to dihydrotestosterone (DHT)

• May act to increase the metabolism and excretion of dihydrotestosterone (DHT) through inhibition of cellular and nuclear receptor binding

• Shown to be as effective as finasteride (Proscar) without the loss of libido as a side effect

Effects of the lipidosterolic extract of Serenoa repens (Permixon) on human prostatic cell lines. Prostate. 1996 Oct; 29(4): 219‐30.Comparison of finasteride (Proscar), a 5 alpha reductase inhibitor, and various commercial plant extracts in in vitro and in vivo 5 alpha reductase inhibition. Zhong Xi Yi Jie He Za Zhi. 1989 Dec; 9(12): 737‐8, 710.

Stinging Nettle Root Urtica dioica

• Displaces testosterone from SHBG binding sites, rendering more free (bioavailable) hormone

• Works to inhibit aromatase activity, preventing testosterone from converting to estrogen

• Interferes SHBG binding with receptors in the prostate that activate androgen receptors

Rhodes L, et al. Comparison of finasteride (Proscar), a 5 alpha reductase inhibitor, and various commercial plant extracts in in vitro and in vivo 5 alpha reductase inhibition. Prostate. 2006; 22: 43‐51.Koch E. Extracts from fruits of saw palmetto (Sabal serrulata) and roots of stinging nettle (Urtica dioica): viable alternatives in the medical treatment of benign prostatic hyperplasia and associated lower urinary tracts symptoms. Planta Med. 2001; 67: 489‐500.

DIM/Indole 3 carbinol (I3C)

• Compounds found in cruciferous vegetables.• I3C converts into DIM in the stomach if there is sufficient acidity

• DIM blocks aromatization of testosterone into estrogen; thus, enhances testosterone levels

• DIM also promotes healthy metabolism of estrogen, treating estrogen dominance

Chang YC, et al. Cytostatic and antiestrogenic effects of 2‐(indol‐3‐ylmethyl)‐3,3'‐diindolylmethane, a major in vivo product of dietary indole‐3‐carbinol. Biochem Pharmacol. 1999; 58: 825‐34.

Hormone Balancing

•Supplement options:•Testosterone•HCG•Progesterone•DHEA

DHEA• DHEA is a precursor to testosterone (and also to estrogen) in the hormone cascade

• DHEA supplementation can be an effective way to raise testosterone levels in hypoandrogenic men

• 25mg/day of DHEA can counteract the age‐related decline of endocrine and neuroendocrine functions

• Doses of 50mg/day may be warranted to boost testosterone levels

Genazzani AR, et al. Long‐term low‐dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency. Aging Male. 2004; 7: 133‐43.

Human Chorionic Gonadotropin(hCG)

•Acts as an LH agonist (and aldosterone:HTN)

•Can be used to boost testosterone without affecting fertility

• Typical protocol is to use:•500 iu SubQ three times/week

Roth MY, et al. Dose‐dependent increase in intratesticular testosterone by very low‐dose human chorionic gonadotropinin normal men with experimental gonadotropin deficiency. J Clin EndocrinolMetab. 2010; 95: 3806‐13.Warne DW, et al. A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle‐stimulating hormone and human chorionic gonadotropin. Fertil Steril. 2009; 92: 594‐604.

Testosterone Replacement Concepts

• In prime, a healthy set of testicles makes 6‐8 mg of testosterone/day

• Testosterone at high doses can suppress endogenous production as well as spermatogenesis. And, receptor down regulation

• Can be safely given topically, sublingually or IM• ORAL—not recommended• I.M. INJECTIONS—testosterone cypionate: 100 mg qwk. HCG combination protocols are available

• TRANSDERMAL—5 to 10 mg/day• Subcutaneous implants

VierhapperH, Nowotny P, WaldhauslW. Determination of testosterone production rates in men and women using stable isotope/dilution and mass spectrometry. J Clin Endocrinol Metab. 1997; 82: 1492‐1496.Rivarola MA, Saez JM, Meyer WJ, Jenkins ME, Migeon CJ. Metabolic clearance rate and blood production rate of testosterone and androst‐4‐ene‐3,17‐dione under basal conditions, ACTH and HCG stimulation. Comparison with urinary production rate of testosteorne. J Clin Endocrinol Metab. 1966 Nov; 26(11): 1208‐18.

Testosterone Replacement• Topical is often compounded with an aromatase inhibitor such as chrysin

• Consider adding progesterone for prostate protection• Careful about excessive dosing due to serum testing

• Sample prescription for male with low T:• Topical testosterone compounded with progesterone and chrysin

• 5‐10mg T/ 10‐20mg Pg/ 50mg chrysin per ml Lipodermbase

• Sig: 1 ml to areas of thin skin qd• DHEA‐ 15mg po qd• Increased fiber intake with goal of 35g qd• 20 minutes of weight bearing exercise 3x/week.

Testosterone Replacement

• Movement toward subcutaneous injections• Testosterone cypionate twice weekly: 50mg (more or less) e.g.: Monday/Thursday

• Draw 0.25cc up with a 1 inch 22g (or larger bore) needle

• Switch to 30g 1 inch needle for injection• Inject slowly into the anterior abdominal fat

Subcutaneous administration• Evaluation of the efficacy of subcutaneous administration of testosterone in female to male transexuals and hypogonadalmales

• T enanthate or cypionate was administered at a dose of 50‐60 mg sc once weekly using 5/8" 23g or 25g needles.

• Serum total T concentrations were measured by tandem mass spectrometry. T levels were well within the therapeutic range varying from 320‐824 ng/dL (mean 608± 82SE).

• No adverse reactions at the site of injection or otherwise were reported or observed

• T was well tolerated and produced therapeutic serum concentrations at doses generally lower than required for IM injections.

Olshan JS, Spack NP, Eimicke T, et al. Poster Board MON‐594. Endocrine Society Annual Meeting 2013.Al‐Futaisi AM, Al‐Zakwani IS, Almahrezi AM, Morris D. Subcutaneous administration of testosterone. A pilot study. Saudi Med J. 2006 Dec; 27(12): 1843‐6.

Testosterone RX RisksTo Patient To Others• Testicular atrophy • Exposure (with topical)• Aggressive behavior• Reduced sperm counts• Erythrocytosis

Controversy

• November 2013 JAMA article concluded that “testosterone supplementation increased risk of adverse cardiovascular events”

• Men in study boosted mean total T level to only 332 ng/dL and only 60% of subjects even had post therapy levels measured

• Estradiol levels were not monitored or reported• Observational and retrospective study, not RCT• ICD‐9 codes used to determine outcomes, not chart review

Vigen R, O’Donnell CL, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013; 310(17): 1829‐36.

Controversy• A second study in early 2014 tracked men for 90 days after starting testosterone therapy and found increased risk of heart attack in men over 65

• No pre or post treatment lab values• Estradiol levels and hematocrit were not monitored or reported

• Observational and retrospective study, not RCT

Finkle W, Greenland S, Ridgeway G, et al. Increased risk of non‐fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE. 2014 Jan 29; 9(1): e85805. doi: 10.1371/journal.pone.0085805.

FDA Warning Label

• As of June 2014 the FDA has added a general warning label regarding potential for venous blood clots to all testosterone products.

• Despite warning, at this time, the FDA “has not concluded that FDA‐approved testosterone treatment increases the risk of stroke, heart attack, or death.”

Safety Announcement. FDA evaluating risk of stroke, heart attack and death with FDA‐approved testosterone products. Available at:http://www.fda.gov/downloads/Drugs/DrugSafety/UCM383909.pdf. Accessibility verified November 18, 2014.

Testosterone and the Cardiovascular System: A Comprehensive Review of the Clinical Literature.

• A review of clinical literature (2013):• “Patients suffering from CAD, CHF, T2DM and obesity have all been shown to have lower levels of endogenous testosterone compared with controls.”

• “Testosterone replacement therapy in men with hypogonadism improves obesity, T2DM, MI, exercise capacity and QTc length.”

Oskui P, French W, Herring M, et al. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc. 2013 Dec; 2(6): e000272.

Refuting articles didn’t make same headlines

• NIH study of over 24,000 patients showed no increased risk of MI in those treated with testosterone

• Found that testosterone use was protective against MI in men with high MI risk

• Also a retrospective study• Study subjects using injectable therapy

Baillargeon J, Urban RJ, Kuo YF, et al. Risk of myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother. 2014 Jul 2; 48(9): 1138‐1144.

Use the lowest dose to achieve clinical response.

Use Of Topical Hormones Can Expose Loved Ones To Elevated Hormones

• 1.8 million prescriptions are written for topical testosterone products annually.

• Unintentional transfer to children or women by skin contact is a recognized side effect.

• Education about proper application technique is important to reduce exposure to household.

Patel A, Rivkees SA. Prenatal virilizationassociated with paternal testosterone gel therapy. Int J Pediatr Endocrinol. 2010; 2010: 867471. Epub 2010 Oct 7.

Many cases of exposure:There are many studies that have shown the effects of secondary exposure to concentrated hormone creams and gels: • C. Brachet, J. Vermeulen, and C. Heinrichs, “Children’s virilization and the use of a

testosterone gel by their fathers,” European Journal of Pediatrics, vol. 164, no. 10, pp. 646–647,2005.

• E. Cohen, O. M. Navarro, E. Reynolds, R. P. Schwartz, and P. Venkataramani, “Index of suspicion,” Pediatrics in Review, vol. 28, pp. 419–425, 2007.

• G. J. Kunz, K. O. Klein, R. D. Clemons, M. E. Gottschalk, and K. L. Jones, “Virilization of young children after topical androgen use by their parents,” Pediatrics, vol. 114, no. 1, pp. 282–284, 2004.

• Y. M. Yu, N. Punyasavatsu, D. Elder, and A. J. D’Ercole, “Sexual development in a two‐year‐old boy induced by topical exposure to testosterone,” Pediatrics, vol. 104, no. 2, p. e23, 1999.

• E. L. Rhoden and A. Morgentaler, “Risks of testosterone replacement therapy and recommendations for monitoring,” New England Journal of Medicine, vol. 350, no. 5, pp. 482–492, 2004.

Dihydrotestosterone(DHT)

DHT: Conventional approach• DHT is the primary contributing factor in male pattern baldness

Piraccini BM. Androgentic alopecia. G Ital Dermatol Venereol. 2014 Feb;149(1):15‐24.

• DHT affects prostate tissue• In benign hypertrophic prostate tissue, DHT levels were 17 times higher than DHT found in other tissues.

• Compared levels to kidney and liver tissue.Albert J, et al. A method for tissue extraction and determination of prostate concentrations of endogenous androgens by radioimmunoassay. J Immunol Methods. 1976;12(3‐4):303‐21.

• Inhibition of DHT in adults results in prostatic shrinkage and symptomatic relief in many men

• “Increased numbers of high‐grade tumors in the finasteridegroup have not yet been fully explained”.Marks LS. 5alpha‐reductase: history and clinical importance. Rev Urol. 2004;6 Suppl 9:s11‐21.

• In a 4 year study, duasteride reduced the incidence of prostate cancer detected on biopsy and improved outcomes related to benign prostatic hyperplasia.

• "There were several limitations that need to be considered when interpreting these results“Andriole GL. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010 Apr 1;362(13):1192‐202.

Dihydrotestosterone‐inducible IL‐6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice.

• Herein we report that the IL‐6 is upregulated in balding DP (dermal papilla) cells compared with non‐balding DP cells. IL‐6 was upregulated 3 hours after 10‐100 nM DHT treatment, and ELISA showed that IL‐6 was secreted from balding DP cells in response to DHT. IL‐6 receptor (IL‐6R) and glycoprotein 130 (gp130) were expressed in follicular keratinocytes, including matrix cells.

• Results strongly suggest that DHT‐inducible IL‐6 inhibits hair growth as a paracrine mediator from the DP.

KwackMH, et al. J Invest Dermatol. 2012 Jan; 132(1): 43‐9. doi: 10.1038/jid.2011.274. Epub 2011 Sep 1.

But is there more to the story?

Fat boosts, while androgen receptor activation counteracts, BPH‐associated prostate inflammation.

• BPH patients (n = 244) who underwent prostatectomy, we evaluated whether MetS is associated with prostatic inflammation in BPH specimens.

• Inflammatory infiltrates score (IS) showed a step‐wise association with the number of MetS factors.

• Reduced HDL cholesterol, and elevated triglycerides were the significantly associated with IS.

• Increased IS significantly associated with hypogonadism.• Oxidized low‐density lipoprotein (oxLDL) showed the highest secretion of IL‐8 (>10‐fold)‐a surrogate marker of prostate inflammation‐‐as well as IL‐6, and bFGF (basic fibroblastic growth factor).

• DHT significantly inhibited oxLDL‐induced secretion of IL‐8. AR‐antagonist, bicalutamide, reversed DHT effects. DHT suppresses oxLDL receptor (LOX‐1) expression.

• T‐via its conversion into DHT‐may have unexpected beneficial effects on prostate health.

Vignozzi L, et al. Prostate. 2013 Jun; 73(8): 789‐800. doi: 10.1002/pros.22623. Epub 2012 Nov 28.

Androgen receptor enhances entosis, a non‐apoptotic cell death, through modulation of Rho/ROCK pathway in prostate cancer cells.• Entosis, which is a newly found homogeneous cell‐in‐cell phenomenon and a non‐apoptosis cell death progress, has unclear function in prostate cancer progression. Here, we dissected mechanism of AR signaling related to entosis incidence in PCa progression.

• Androgen‐DHT could enhance entosis• Conclusions: AR might play a negative role during PCa progression via influencing entosis by modulating Rho/ROCK pathway. This newly identified AR role of enhancing entosis might help us to better understand the multiple and opposite roles of AR, which could either promote or suppress PCa cell progression via different mechanisms.

Wen S, et al. Prostate. 2013 Sep; 73(12): 1306‐15. doi: 10.1002/pros.22676. Epub 2013 Jun 15.

Increased DHT levels in androgenic alopecia have been selected for to protect men from prostate cancer.

• Androgenic alopecia, a condition characterized by increased levels of DHT could have been selected for due to the benefits that prostaglandin D2 (PGD(2)) has on the prostate. A DHT metabolite can increase the transcription of prostaglandin D2 synthase through estrogen receptor beta. The increase of PGD(2) can decrease the risk of prostate cancer and proliferation of prostate cancer cells. Therefore, the mechanisms behind male pattern baldness may also curtail the advancement of prostate cancer.

Bhargava S. Med Hypotheses. 2014 Apr; 82(4): 428‐32. doi: 10.1016/j.mehy.2014.01.016. Epub 2014 Jan 26.

The dark side of 5α‐reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression.• Finasteride and dutasteride approved by the U.S. Food and Drug Administration for the treatment of BPH symptoms.

• Adverse side effects of 5α‐RIs on sexual function, high grade prostate cancer incidence, central nervous system function and on depression.

• 5α‐Rs distributed in many tissues including the central nervous system and inhibition of these enzymes results in blockade of synthesis of several key hormones and neuro‐active steroids.

• Loss of or reduced libido, erectile dysfunction, orgasmic dysfunction, increased high Gleason grade prostate cancer, observed heart failure and cardiovascular events in clinical trials.

• Significant and serious adverse effects of 5α‐Ris on sexual health, vascular health, psychological health and the overall quality of life.

Traish AM, et al. Korean J Urol. 2014 Jun; 55(6): 367‐79. doi: 10.4111/kju.2014.55.6.367. Epub 2014 Jun 16.

Monitoring RX Therapy

• Saliva*• Testosterone• Estradiol• Progesterone• Pg/E2 ratio

• Serum• CBC (hematocrit)• Fasting glucose• PSA

* Salivary levels are the only way to effectively monitor topical therapy.

Take Home Nuggets

• Waist circumference increase is a significant indicator of metabolic syndrome

• Metabolic syndrome is and will be a major health problem for the US population and may be at root of MANY other disease processes

• Metabolic syndrome is reversible• Testosterone supplementation should be considered if insufficiency is established

• Testosterone is not the cause of prostate cancer

Take Home Nuggets

• Insulin resistance in the male is related to a relative testosterone deficiency

• Males become estrogen dominant with ageleading to BPH and prostate cancer

• Progesterone is the antidote to estrogen dominance

• Boosting testosterone is safe and may be life saving

• Herbal supplementation is a helpful adjunct• DHT may be beneficial to prostate health

Documents

AdvancedMensNaturalHormoneBalancing JM …...Testosterone Declines at 1.6% Per Year Starting at Age 30! So at an age when many men are just figuring out what they want to be when they